Nonmyeloablative conditioning with low dose TBI (2 Gy) +/- fludarabine (30 mg/m2 x 3) and post grafting immunosuppression with cyclosporine and mycophenolate mofetil provides reliable engraftment for allogeneic G-CSF mobilized peripheral blood stem cells from HLA matched related or unrelated donors. This results in full donor chimerism and provides immunologic graft-vs-tumor (GVT) effects. Indeed, with this platform, nearly all of the anti-tumor activity comes from GVT immune responses with little contribution from the conditioning regimen. Our results demonstratethat this response may provide long term anti-tumor activity in many patients with B cell malignancies with outstanding activity noted in patients with low-grade non-Hodgkin Lymphoma (NHL), mantle cell NHLand chronic lymphocytic leukemia (CLL). Limitations of this approach were also evident as patients with aggressive, bulky or rapidly proliferating disease may develop tumor progression before the development of, or despite GVT effects. The focus of Project 4 is to augment the anti-tumor effect of nonmyeloablative conditioning for the treatment of B cell malignancies by improving pre-transplant cytoreduction, augmenting allogeneic GVT effects and incorporating additional agents with anti tumor activity, and limited toxicity. Lastly, we plan to expand this approach to patients without HLA matched related or unrelated donors by using a newprotocol that allows successful engraftment of related HLA haploidentical grafts. The Specific Aims are to use: 1. Tandem transplants using cytoreductive high-dose therapy and autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT from : a. HLA matched allogeneic HCT from related or unrelated donors for lymphoma. b. HLA matched allogeneic HCT from related or unrelated donors followed by maintenance therapy with bortezomib for high risk or relapsed Multiple Myeloma (MM).; c. HLA haploidentical allogeneic HCTfrom related donors for relapsed or refractory lymphoma. 2. Addition of targeted therapies to nonmyeloablative conditioning with Flu/TBI followed by allogeneic HCT from HLA matched related or unrelated donors: a. Monomethyl Aurostatin E conjugated anti-CD30 antibody (SGN35) for relapsed or refractory HL. b. Tyrosine kinase inhibitors for Philadelphia chromosome positive leukemia. c. Anti-CD20 antibody Rituximab for CD20 positive B cell NHL and fludarabine refractory CLL. The public health benefits of this Project are that patients with various malignant blood disorders who . otherwise would have been excluded because of age and comorbidities have benefited from treatment by allogeneic HCT. Inaddition, the use of HLA-haploidentical donors will extend the option of HCT to a greater number of patients, including ethnic minorities.